Vaccines against various and evolving strains of influenza are important not only from a community health stand point, but also commercially, since each year numerous individuals are infected with different strains and types of influenza virus. Infants, the elderly, those without adequate health care and immuno-compromised persons are at special risk of death from such infections. Compounding the problem of influenza infections is that novel influenza strains evolve readily, thereby necessitating the continuous production of new vaccines.
Numerous vaccines capable of producing a protective immune response specific for such different influenza viruses have been produced for over 50 years and include, e.g., whole virus vaccines, split virus vaccines, surface antigen vaccines and live attenuated virus vaccines. However, while appropriate formulations of any of these vaccine types are capable of producing a systemic immune response, live attenuated virus vaccines have the advantage of being also able to stimulate local mucosal immunity in the respiratory tract. A vaccine comprising a live attenuated virus that is capable of being quickly and economically produced and that is capable of easy storage/transport is thus quite desirable. Also desirable would be methods to increase production of such viruses, and thus of vaccines for such viruses, especially for virus strains that have proven difficult to produce and/or scale up for commercial production using traditional methods.
To date, all commercially available influenza vaccines in the United States have been propagated in embryonated hen eggs. Although many influenza virus strains grow well in hen eggs, the production of vaccine is dependent on the availability of such eggs. Because the supply of eggs must be organized, and strains for vaccine production selected months in advance of the next flu season, the flexibility of this approach can be limited, and often results in delays and shortages in production and distribution. Also, various influenza virus strains grow less well in eggs (e.g., do not produce as high a titer) as other influenza strains. Therefore, methods to increase production, e.g., of desired strains of such viruses, and thus vaccines, are greatly desirable.
Systems for producing influenza viruses in cell culture have also been developed in recent years (See, e.g., Furminger. Vaccine Production, in Nicholson et al. (eds.) Textbook of Influenza pp. 324-332; Merten et al. (1996) Production of influenza virus in cell cultures for vaccine preparation, in Cohen & Shafferman (eds.) Novel Strategies in Design and Production of Vaccines pp. 141-151). However, such systems can also involve production or scale-ups in eggs and so can also encounter productivity issues, especially in regard to specific strains. Therefore, any methods to increase virus/vaccine production in these systems as well are also greatly desirable.
Considerable work in the production of influenza virus for production of vaccines has been done by the present inventor and co-workers; see, e.g., PCT Publications WO 03/091401, WO 05/014862, and PCT Patent Applications PCT/US05/017734, filed May 20, 2005, and PCT/US05/035614, filed Oct. 4, 2005. The present invention provides methods of increasing production of influenza viruses and virus compositions for production of vaccine compositions. Aspects of the current invention are applicable to traditional hen egg and new cell culture vaccine production styles (and also combined systems) that comprise steps of virus growth in hen eggs, and comprise numerous other benefits that will become apparent upon review of the following.